1. Field of the Invention
This invention relates to 3,5,6-substituted derivatives of 1,2-O-isopropylidene-.alpha.,D-glucofuranose compounds and intermediates for preparing these derivatives. More particularly, this invention relates to derivatives of 1,2:3,5-Di-O- and 1,2:5,6-Di-O-isopropylidene-6-deoxy-.alpha.,D-glucofuranose. It also relates to furanosides obtained when 1,2-O-isopropylidene residues are reacted with methanol or other aliphatic alcohols of up to seven carbon atoms, both branching and containing double bonds. It further encompasses glucofuranose and related hexofuranose compounds wherein chirality is changed at positions 3 and 5. The derivatives of this invention have anti-proliferation and anti-inflammatory activity and are useful for treating animals and mammals with inflammatory and/or autoimmune disorders such as autoimmune deficiency syndrome, psoriasis, atopic dermatitis, rheumatoid arthritis, osteoarthritis, scleroderma and systemic lupus erythematosus.
2. Description of the Related Art
Blocked acetals of hexoses exist as solids or liquids at room temperature. Various blocking methods are described in U.S. Pat. Nos. 2,715,121 and 4,056,322, the disclosures of which are incorporated by reference herein in their entireties. For example, in instances where an aldehyde or ketone is reacted with the hydroxyl groups on adjacent or neighboring sugar carbon atoms, the hexose may be blocked in a plurality of positions, such as, e.g., the 1,2- and/or 5,6- positions. In the 1,2:5,6-blocked hexoses the ring forms between carbons 1 and 4, leaving carbon 3 free to etherize and in the 1,2:3,5-blocked hexoses, the ring forms between carbons 1 and 4, leaving carbon 6 free to etherize. Thus, 1,2:5,6-blocked hexoses may form 3-O ethers, and 1,2:3,5-blocked hexoses may form 6-O ethers. After the desired blocking of the monosaccharide is obtained, the unblocked position of the monosaccharide can be etherized.
The 3- and 6-substituted furanoses thus obtained are generally known to have anti-inflammatory activity. Specific therapeutic compounds such as amiprilose hydrochloride, 1,2-O-Isopropylidene-3-O-3('N,N'-dimethylamino-n-propyl)-.alpha.,D-glucofu ranose (i.e. THERAFECTIN.RTM.), have been known for some time. This compound has demonstrated utility in managing the signs and symptoms of rheumatoid arthritis while exhibiting little toxicity. It is generally known that furanose compounds have activity as immuno-modulators, and therefore, may have a therapeutic effect on other autoimmune disorders such as psoriasis, eczema or lupus. For certain of these indications, high doses of these monosaccharides, such as THERAFECTIN.RTM., are needed to produce effective results. Consequently, they are difficult to prescribe orally. As therapy for those conditions is often midterm or longterm, there is a need to develop potent, non-toxic compounds which can be orally administered to promote patient compliance.
It is therefore an object of the present invention to provide substituted 1,2-O-isopropylidene-.alpha.,D-glucofuranose compounds that exhibit significantly greater potency than available compounds, such as THERAFECTIN.RTM., in order to provide ease of oral administration. It is believed that the compounds of the present invention act by a different mechanism than THERAFECTIN.RTM. and are more selective in their activity.
Additional objects and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the mechanisms and combinations pointed out in the appended claims.